The development of cancer is a multistep process involving multiple genetic changes that lead to the malignant state. These genetic changes occur in molecules involved in the most basic decisions that a cell must make, namely proliferation, differentiation and cell death. In order to understand cancer more fully, it is important to analyze how these molecules function in normal cells and how their functions are perturbed in cancer. The central theme of this program is the analysis of signaling pathways that control cellular growth, differentiation, and cell survival, and how these signals are directed from the cytoplasm to the nucleus where transcriptional changes enact growth regulatory signals. The goal of the program is to understand the molecular mechanisms of specificity that direct proliferative signals from the cell surface, through the cytoplasm, and into the nucleus. Our Program consists of vie investigators in the School of Medicine at the State University of New York at Stony Book whose research focuses on signal transduction and gene regulation. During the past twenty years, our Program has evolved from a study of tumor virus-associated oncogenes to our present emphasis on signal transduction and the regulation of cell growth. The research projects described in the proposal are: Project 1: Positive and Negative Regulation of RTK-Ras Signaling Project 2: Role of Growth Factor Receptors in Hematopoietic Malignancies Project 3: Regulation of Transcription Factor E2F Project 4: Determinants of Tyrosine Kinase Specificity Project 5: Cytokine Signaling to the Nucleus Core 1: Administration Core 2: Sequencing Core 3: Protein Expression